The FK506-binding protein (FKBP) family of immunophilins consists of proteins with a variety of protein-protein interaction domains and versatile cellular functions. This highly conserved protein family binds with immunosuppressive drugs, such as FK506 and rapamycin. This protein family displays peptidyl propyl isomerase (PPIase) activity as seen with cyclophilins and parvulins. FKBP12, a 12 kD protein is the most widely studied member of this family.
The immunosuppressant drugs FK506, rapamycin, and cyclosporin are well known as potent T-cell specific immunosuppressants, and are effective against autoimmunity, transplant or graft rejection, inflammation, allergic responses, other autoimmune or immune-mediated diseases, and infectious diseases.
FK506 and rapamycin apart from binding to FKBP12 also interact and inhibit calcineurin (CaN) and mTOR respectively thereby mediating their immunosuppressive action.
The high molecular weight multidomain homologs of FKBP12, FKBP51 and FKBP 52, act as cochaperones for the heat shock protein 90 (Hsp90) and modulate the signal transduction of the glucocorticoid receptor by participating in the Heat shock protein 90 (Hsp90)-steroid receptor complex.
In this complex, FKBP51 and FKBP52 modulate the binding competence and signalling of steroid hormone receptors and thereby regulate the cellular responsiveness to circulating hormone levels. This is supported by a natural animal model (squirrel monkey) and by knockout mice, where the crucial role of FKBP51 and FKBP52 on the Glucocorticoid Receptor (GR) Progesterone Receptor (PR) or Androgen Receptor (AR) activity have been clearly demonstrated. Moreover, polymorphisms in the FKBP51-encoding gene of psychiatric patients have been associated with numerous stress-related psychiatric disorders (Schmidt et al., ChemMedChem 2012, 7, 1351-1359).
The immunosuppressive compounds disclosed in the prior art suppress the immune system, by definition, and also exhibit other toxic side effects. Accordingly, there is a need for non-immunosuppressant, small molecule compounds, and compositions and methods for use of such compounds, that are useful in treating psychiatric disorders and neurodegenerative diseases, disorders and conditions.
FKBP51 and FKBP52 have repeatedly been shown to regulate biological processes in opposite directions. Most importantly, FKBP51 and FKBP52 antagonize each other in the regulation of the glucocorticoid receptor and other steroid hormone receptors (Storer, C. L.; Dickey, C. A.; Galigniana, M. D.; Rein, T.; Cox, M. B., FKBP51 and FKBP52 in signaling and disease. Trends Endocrinol Metab 2011, 22, (12), 481-90). Therefore, there is a strong need for selective inhibitors that can discriminate between FKBP51 and FKBP52 (Schmidt et al ChemMedChem 2012, 7, 1351-1359). There is also a strong need for drugs to treat neuronal atrophy or degeneration or to enhance neurogenesis in diseases like depression, physical nerve injury and Alzheimer's, Huntington's, Parkinson's disease, ischemia or traumatic brain injury.
Selective inhibition of FKBP51 versus FKBP52 by small molecule inhibitors is very important to obtain more beneficial effects in these disorders. Selectivity between FKBP51 and FKBP52 represents a huge and unsolved hurdle, since the residues within the active site are completely conserved both on the sequence and the structural level (Bracher, A.; Kozany, C.; Thost, A. K.; Hausch, F., Structural characterization of the PPIase domain of FKBP51, a cochaperone of human Hsp90. Acta Crystallogr D Biol Crystallogr 2011, 67, (Pt 6), 549-59). Indeed, all known ligands for FKBP51 or FKBP52 show only negligible selectivity between these two FKBP homologs. The present invention describes the first ligands that are selective for FKBP51 compared to FKBP52. This selectivity for FKBP51 translates into an improved stimulation of neuritogenesis. The selectivity for FKBP51 is achieved by a conformational change in FKBP51 that is induced by the described FKBP51-selective ligands, which are much less favourable for FKBP52. This induced fit is the basis for rational design and synthesis of selective FKBP51 inhibitors.
It is the object of the present invention to provide compounds and/or pharmaceutically acceptable salts thereof which selectively inhibit FKBP51 but which show no immunosuppressive activity and improved stimulation of neuritogenesis.
A further aspect of the invention is to provide compounds and/or pharmaceutically acceptable salts thereof which can be used as pharmaceutically active agents, especially for the treatment of psychiatric disorders and neurodegenerative diseases, cancers like prostate cancer, acute lymphoblastic leukaemia or malignant melanoma, obesity, metabolic syndrome, diabetes, asthma, sleeping disorders, vision disorders and/or improving vision, for treating memory impairment and/or enhancing memory performance and for treating alopecia, as well as compositions comprising at least one of those compounds and/or pharmaceutically acceptable salts thereof as pharmaceutically active ingredients.
Furthermore, it is the object of the present invention to provide methods for identifying, optimizing and designing compounds as selective inhibitors of FKBP51 based on the structural information specific for the induced fit conformation, which is the underlying basis for the FKBP51-selectivity.
The object of the present invention is solved by the teaching of the independent claims. Further advantageous features, aspects and details of the invention are evident from the dependent claims, the description, and the examples of the present application.